Molecular Modelling and Biochemical Evidence to Explore Potentials of Chewing Tobacco in Drug Resistance and Cancer Induction

摘要

Industrial workers have exposure to several compositemixtures, heavy organo-metallic complexes and they also consumetobacco (by smoking and chewing). The habit of smoking or chewingtobacco is linked to an unprecedented rise in lung cancer cases inlabour class. The carcinogenic effects of tobacco were initiallythought to be restricted to the lungs and the adjoining areas, butrecent studies indicate that tobacco also aggravates cancer of theliver, stomach and cervix. In the present study, we explored themolecular mechanism of the role of chewing tobacco in thedevelopment of drug resistance and cancer induction. Tobacco leavesare consumed in Indian society, and the samples of these leaves wereprocured from 20 different cities of India. Interestingly, culturingbreast cancer cells in tobacco leave extract (100μg/ml) for severalgenerations follow a trend towards acquiring resistance foranticancer drug mitomycin C., In addition, these cells are showing ahigher level of matrix metalloprotease gelatinase activity. Secretionof MMPs is the hallmark of metastatic and invasion phenotype ofcancer cells. Protein kinase C is the master regulator of severalsignalling pathways contributing into metastasis and invasion ofcancer cells. Tobacco contains ~120 biologically activephytochemicals, and virtual screening was performed with the C1bdomain of PKC-α as the drug target. Several phytochemicals fit wellinto PKC with high affinity. Phytosterols are found in the prominentcandidate molecules, and these molecules might have a crucial rolein potentiating the metastatic activity of cancer cells. Hence, a virtualscreening experiment complemented with in-vitro studies haveassigned an additional role to the phytochemicals present in thetobacco, and these finding may help clinicians to redesign their anticancer therapy.